Seite - 119 - in Advances in Neuroimmunology

BrainSci. 2016,6, 23 Underphysiologicalconditions, theBBBendothelialcellsandcomponentsof theextracellularmatrix supportOPCsurvival,andpromoteneuralprogenitorcells (NPC)differentiate toneurons,astrocytes, andoligodendrocytes [51–53]. Thecritical functionofBBBandtheconsequencesofBBBdisruptionimply its involvement inHIV-1-associatedoligodendrocyte/myelin injury. It isnotsurprisingthat thedisrupted BBBpromotestheentranceofviruses, infectedTcells,andtoxicsubstancesfromthebloodtothebrain, resulting inOPC/oligodendrocyte/myelin injury. Inhibition ofOPCproliferation canbe causedby plasma,serum,thrombin,andplasmininprimaryculture. Thrombinalsosuppresses thedifferentiation ofOPCs intomature oligodendrocytes [54]. In addition, elevated levels of TNF-α, an inflammatory cytokinepromotingoligodendrocytedeath [55],weredetected inbloodmononuclearphagocytes in HIV-infectedpatients [56].HIV-1 infectionalso induces interleukin(IL)-1βproductionfrommononuclear phagocytes [57]. IL-1βpromotesoligodendrocytedeath throughglutamateexcitotoxicity [58]. These findingssuggest thatBBBdisruptioncontributes toHIV-1-associatedmyelin/oligodendrocytedamage. 5.CellularMechanismsforOligodendrocyteInjuryinHIV-1-InfectedBrain Apoptotic signalactivationofoligodendrocyteshasbeenobservedinHANDpatients [59]. Such anapoptoticactivationofoligodendrocytescouldbecauseddirectlybyHIV-1viralproteinsor induced indirectlyby immuneandinflammatoryfactors. It iswell-known that tumor suppressor p53 induces apoptosis by activating transcription of variouspro-apoptoticgenes[60].Activationofp53wasdetectedintheoligodendrocyte lineagecells in thebrainsofHANDpatients,butnot incontrolbrains [59].Dueto thedifficulties indistinguishingthe differentiatingstagesofoligodendrocytelineageonautopsysamples, thedetectedp53reactivityreflects apoptosisofmatureoligodendrocytesandOPCs. Thesesuggest that, inadditiontooligodendrocyte injury,proliferationofOPCs isalso impaired inHAND. Gp120wasshowntocauseslowbutprogressiveoligodendrocytecytosolicCa2+ rise inamixed culture of cerebellar cortex cells [41] and the rise of introcellular Ca2+ concentrationmay trigger oligodendrocyticapoptosis. Exposureofoligodendrocytes toTatalsoproducedarapid increase in intracellularCa2+ levels throughNMDAandα-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA)receptors, causingoligodendrocyte injury. It isworthmentioningthat therolesofNMDAand AMPAreceptorsappear tobedifferentanddependentonthestageofOPCdifferentiation. Tat-induced OPCdeathcanbeblockedbyeitherNMDAorAMPAreceptorantagonists.However,Tat’sdetrimental effects onmature oligodendrocytes canonlybe reversedbyNMDAreceptor antagonists, but not AMPAreceptor blockade [6]. Tatwas also found to cause oligodendrocyte apoptosis invitro and myelin injury exvivobyenhancingvoltage-dependentK+ channel (Kv)1.3activity [61]. The lossof K+ ionsmaycausecell regulatoryvolumedecrease (shrinkage), leading tocell apoptosis [62]. The involvementofTat inoligodendrocyteapoptosishasbeendemonstrated inanHIV-1Tat transgenic mousemodel. Theoligodendrocyteswithin the striatumexhibit ahigh sensitivity tomorphine in HIV-1Tat transgenicmiceandtheyare theonlyapoptotic cell type inresponse tocombinedmorphine exposureandTat induction inTat transgenicmice [9]. Tatalso interactswithmorphine todecrease the proliferationofOPCs[63].Opioidabuseproducessynergistic toxicactivity inHIV-1-infectedbrains bydirectactionsonimmatureastrocytesandoligodendrocytes,whichexpressμ-opioidorκ-opioid receptors [64]. Inotherviral-induceddemyelination, thereisclearevidencethatmousehepatitisvirus(MHV)can directly infectandactivatemicrogliaduringacuteinflammation,whicheventuallycausesphagocytosis of themyelinsheath, leadingtodemyelinationduringthechronic inflammationstage [65].Asimilar theoryhasbeenproposedformultiplesclerosis,which is themostprevalentdemyelinatingdisease, that immune-activatedmicrogliastrip themyelin. Recentevidencehasshownthatmicrogliabecome phagocytic in response toHIV-1 Tat [66,67]. Itmight be possible that the infected and activated microgliaphagocyteoligodendrocytesandmyelinsheath leadto themyelindamageandconsequent HAND pathogenesis, although there is no direct evidence indicating microglia phagocytosis of oligodendrocyte inneuroHIV[68]. 119